The chemistry and interactions of the complement (C) attack proteins (C5-C9) are reasonably well defined, but the control of this powerful biological effector system is not as well understood. It is the aim of this proposal to approach the study of control of the C attack system from two different aspects. First, studies on the inhibition of the action of the C5b67 complex by serum proteins will be continued. The roles of C8 and its subunits, lipoproteins and their apoprotein constituents, and other potential serum inhibitors (S protein) will be quantified and defined by preparing serum reagents free of these activities. Results will be confirmed using purified, radiolabeled C components. To demonstrate the potential in vivo relevance of these control mechanisms, additional studies will be performed in whole serum systems in which zymosan or immune complexes are used to activate the C attack mechanism. The relative effectiveness of C5b67 attachment to guinea pig erythrocytes in sera depleted of various C567 inhibitors will be evaluated by functional (lytic) and radioisotope tracer methods. The second approach will investigate the mechanism by which tumor cells resist C attack. Using labeled C5b6, the fate of C5b67 complexes bound to lymphoblastoid cells will be followed. Clearance of complexes from cells will be correlated with the ability of the C attack proteins to kill the cells. The effects of membrane-bound C3 fragments on the susceptibility of tumor cells to C-mediated cytotoxicity will be quantitatively assessed and correlated with the specific binding of labeled C components to the target cell. This study represents one of the first investigations into the interaction between the isolated human C attack proteins and human nucleated cells, and as such, may produce fundamental new information on the role of the complement attack mechanism in the destruction of tumor cells.